During the past year we have published a detailed analysis of the B cell response in HCV-infected patients with and without mixed cryoglobulinemia (MC), and the impact of rituximab treatment on B cell function in these patients. MC, the most common of the B-cell abnormalities in HCV-infected patients, is characterized by clonal proliferation of B-cells and the formation of cold-precipitable cryoglobulin complexes composed of IgM antibodies with rheumatoid factor activity. Despite activation and clonal expansion of B-cells in chronic HCV infection we observed a reduction in the total number of B cells and in the size of the naive B cell subset in patients with MC compared to HCV-infected patients without MC and healthy controls. The reduced frequency of naive B cells in HCV-infected patients with MC was associated with decreased ex vivo expression of the antiapoptotic protein Bcl-2 compared to HCV-infected patients without MC and healthy controls, and with an increased in vitro sensitivity of naive B-cells to apoptosis. These results provide mechanistic data on the death of naive B-cells to a previous study by Cacoub et al. who reported a decreased naive B-cell frequency in untreated MC patients but did not examine the underlying mechanism (Blood 2008;111:5334-5341). As naive B-cells comprise approximately 70% of all B-cells, their rapid turnover may trigger the release of immature B-cells from the bone marrow. Indeed, we observed four-fold expansion and skewing (lower T1/T2-ratio) of the immature B-cell subset in HCV-infected patients with MC. This immature subset is important following treatment with rituximab as during the initial stages of B cell reconstitution these cells comprised the majority of B-cells. Based on the observed reduction of CD19+ B-cell percentages and numbers, and the increased apoptosis susceptibility of their main fraction, the naive B-cell population, we propose that the increased size of the immature B-cell subset is due to a secondary egress from the bone marrow to compensate for the B-cell loss in the periphery. This process may be mediated by BAFF, a B-cell growth factor that is elevated in the plasma of HCV patients (J Immunol 2010; 185:3019-3027; Ann Rheum Dis 2009;68:337-344).